IL-2 consumption by highly activated CD8 T cells induces regulatory T-cell dysfunction in patients with hemophagocytic lymphohistiocytosis
IL-2 consumption by highly activated CD8 T cells induces regulatory T-cell dysfunction in patients with hemophagocytic lymphohistiocytosis
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DOI：
10.1016/j.jaci.2015.12.1314
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发表时间：
2016-07-01
影响因子：
14.2
通讯作者：
Liston, Adrian
中科院分区：
文献类型：
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作者：
Humblet-Baron, Stephanie;Franckaert, Dean;Liston, Adrian
背景：噬血细胞性淋巴组织细胞增生症（HLH）是一种严重的炎症性疾病，由过度的CD 8（+）T细胞活化引起。HLH以获得性和家族性噬血细胞性淋巴组织细胞增生症（FHL）形式发生。在这两种情况下，疾病的发生都需要一个无菌或感染性的触发因素，然后变得自我维持并危及生命。最近的研究将关键的远端事件归因于IFN-γ的过度产生;然而，驱动免疫失调的近端事件仍然不确定。目的：我们试图研究调节性T（Treg）细胞在实验性FHL的病理生理学中的作用。因为穿孔素突变是FHL的常见原因，我们使用了实验性FHL小鼠模型，其中穿孔素缺陷小鼠的疾病由淋巴细胞性脉络丛脑膜炎病毒（LCMV）触发。我们评估了Treg和CD 8（+）T细胞在小鼠全身条件变化期间的稳态和活化。此外，人类血液样本收集和分析HLH epission.Results：我们没有发现原发性Treg细胞缺陷穿孔素缺陷小鼠。然而，Treg细胞数量在LCMV接种后崩溃。在LCMV触发的穿孔素缺陷小鼠中Treg细胞数量的崩溃，但不是野生型小鼠，伴随着常规CD 4（+）T细胞的IL-2分泌降低，活化的CD 8（+）T细胞的IL-2消耗增加以及竞争性可溶性CD 25的分泌。结论：这些结果表明，过度的CD 8（+）T细胞活化使IL-2稳态网络从Treg细胞的维持向前馈炎症的方向重新连接。这些结果也为HLH患者的感染性炎症进展为持续性炎症提供了潜在的机制途径。
Background: Hemophagocytic lymphohistiocytosis (HLH) is a severe inflammatory condition driven by excessive CD8(+) T-cell activation. HLH occurs as both acquired and familial hemophagocytic lymphohistiocytosis (FHL) forms. In both conditions, a sterile or infectious trigger is required for disease initiation, which then becomes self-sustaining and life-threatening. Recent studies have attributed the key distal event to excessive IFN-gamma production; however, the proximal events driving immune dysregulation have remained undefined.Objective: We sought to investigate the role of regulatory T (Treg) cells in the pathophysiology of experimental FHL.Methods: Because mutation in perforin is a common cause of FHL, we used an experimental FHL mouse model in which disease in perforin-deficient mice is triggered by lymphocytic choriomeningitis virus (LCMV). We assessed Treg and CD8(+) T-cell homeostasis and activation during the changing systemic conditions in the mice. In addition, human blood samples were collected and analyzed during the HLH episode.Results: We found no primary Treg cell defects in perforin-deficient mice. However, Treg cell numbers collapsed after LCMV inoculation. The collapse of Treg cell numbers in LCMV-triggered perforin-deficient, but not wild-type, mice was accompanied by the combination of lower IL-2 secretion by conventional CD4(+) T cells, increased IL-2 consumption by activated CD8(+) T cells, and secretion of competitive soluble CD25. Moreover low Treg cell numbers were observed in untreated patients experiencing HLH flares.Conclusion: These results demonstrate that excessive CD8(+) T-cell activation rewires the IL-2 homeostatic network away from Treg cell maintenance and toward feed-forward inflammation. These results also provide a potential mechanistic pathway for the progression of infectious inflammation to persistent inflammation in patients with HLH.